The compound (1) is a therapeutic agent against hepatitis B (Korean Patent Application No. 2002-0003051, WO 02/057288), and the compound (2) can be used as an important reactant together with a compound of the following formula (3):
in which X represents fluorine, chlorine, bromine, or iodine, for preparing the compound (1).
Such purine derivatives as the compound (1) are known to have anticancer and antiviral activities, and ten (10) or more kinds of such derivatives including AZT, 3TC, ACV, etc. are already commercially available.
The compound (2) used as an important intermediate for preparing the compound (1) has been prepared according to the process depicted in the following Reaction Scheme 1:
The above process of Scheme 1 uses ethyl glycolate of the following formula (4):
as a starting material.
In the process of Scheme 1, ethyl glycolate of formula (4) is combined with t-butyl(diphenyl)silyl chloride to give the compound of formula (5), which is reacted with ethyl magnesium bromide and titanium tetraisopropoxide according to the process (Syn. Lett, 07, 1053-1054, 1999) known in the art to give the cyclopropyl alcohol compound of formula (6), which is then obtained as a solid from heptane. Thus obtained compound of formula (6) is dissolved in dimethylformamide and reacted with lithium t-butoxide and diisopropylbromomethyl phosphonate to give the compound of formula (7). This compound of formula (7) is refluxed with ammonium fluoride in methanol to give the compound (2).
The above process, however, has the demerit of giving an impure form of compound (2) because diisopropylbromomethyl phosphonate used in the step of synthesizing the compound of formula (7) is remained in the reaction solution, and so always included in the finally obtained compound (2) in an amount of 7˜15%. Further, poor stability of the compound of formula (6) against lithium t-butoxide during the step of synthesizing the compound of formula (7) are responsible for varied yield and difficult handling.
Therefore, it has been desired for those skilled in the art to raise purity of the compound (2) and to improve stability of the compound of formula (6) during synthesis of the compound of formula (7).